IFN-γ producing T cells contribute to the increase of myeloid derived suppressor cells in tumor-bearing mice after cyclophosphamide treatment

Guo, Qingming; Lv, Zhangchun; Fu, Qihong; Jiang, Chao; Liu, Yang; Lai, Lihua; Chen, Qing‐Yun; Shen, Jian Qi; Wang, Qingqing

doi:10.1016/j.intimp.2011.12.016

Cited by 16 publications

(13 citation statements)

References 30 publications

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“…29 Dextramer staining for R9F-specific CD8 C T cells also confirmed the presence of antigen-specific CD8 C T cells among lymph node cells from mice treated with DPX-R9F vaccine combined with mCPA or sbCPA (Fig. 1D).…”

Section: E953407-2 Volume 3 Issue 8 Oncoimmunologysupporting

confidence: 56%

Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response

et al. 2014

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In clinical trials, metronomic cyclophosphamide (CPA) is increasingly being combined with vaccines to reduce tumor-induced immune suppression. Previous strategies to modulate the immune system during vaccination have involved continuous administration of low dose chemotherapy, studies that have posed unique considerations for clinical trial design. Here, we evaluated metronomic CPA in combination with a peptide vaccine targeting HPV16E7 in an HPV16-induced tumor model, focusing on the cytotoxic T-cell response and timing of low dose metronomic CPA (mCPA) treatment relative to vaccination. Mice bearing C3 tumors were given metronomic CPA on alternating weeks in combination with immunization with a DepoVax vaccine containing HPV16E749–57 peptide antigen every 3 weeks. Only the combination therapy provided significant long-term control of tumor growth. The efficacy of the vaccine was uncompromised if given at the beginning or end of a cycle of metronomic CPA. Metronomic CPA had a pronounced lymphodepletive effect on the vaccine draining lymph node, yet did not reduce the development of antigen-specific CD8+ T cells induced by vaccination. This enrichment correlated with increased cytotoxic activity in the spleen and increased expression of cytotoxic gene signatures in the tumor. Immunity could be passively transferred through CD8+ T cells isolated from tumor-bearing mice treated with the combinatorial treatment regimen. A comprehensive survey of splenocytes indicated that metronomic CPA, in the absence of vaccination, induced transient lymphodepletion marked by a selective expansion of myeloid-derived suppressor cells. These results provide important insights into the multiple mechanisms of metronomic CPA induced immune modulation in the context of a peptide cancer vaccine that may be translated into more effective clinical trial designs.

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Section: E953407-2 Volume 3 Issue 8 Oncoimmunologysupporting

confidence: 56%

Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response

et al. 2014

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“…This outcome was significantly reduced due to co-treatment with the A. ferruginea extract. Several studies reported that IL-2, which plays a major role in maturation/development of lymphocytes and monocytes and stimulates natural killer (NK) cell secretion of IFN (Theze et al, 1996) -which in turn stimulates macrophage activation and T-cell differentiation (Borish & Rosenwasser, 1996), is impacted by CTX treatment (Guo et al, 2012). Similarly, GM-CSF, a hematopoietic growth factor pivotal for the regulation of bone marrow progenitor cell proliferation (Gasson, 1991), was also shown to be affected by CTX treatment (Shalit et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Acacia ferrugineainhibits cyclophosphamide-induced immunosuppression and urotoxicity by modulating cytokines in mice

Sakthivel

Guruvayoorappan

2014

Journal of Immunotoxicology

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Cyclophosphamide (CTX), commonly used as an anti-neoplastic drug, can cause adverse sideeffects including immunotoxicity and urotoxicity. Increasingly, plants have become sources of therapeutics that can help to restore host immunity to normal. In this study, Acacia ferruginea was assessed for an ability to protect mice against/mitigate CTX-induced toxicity. Coadministration of an extract of A. ferruginea (10 mg/kg BW, IP daily) for 10 consecutive days reduced CTX (25 mg/kg BW, IP daily)-induced toxicity. Apart from improvements in bladder and small intestine morphology, there was marked improvement in anti-oxidant (glutathione) levels in the bladder, suggesting a role for the anti-oxidant in reducing CTX-induced urotoxicity. Moreover, use of the extract significantly increased total leukocyte counts and bone marrow cellularity/-esterase activity in CTX-treated mice which suggested a protective effect on the hematopoietic system. Co-treatment with the extract also prevented decreases in organ (liver, kidney, spleen, thymus) weight as well as body weight, thereby seemingly lessening the potential impact of CTX on the host immune system. Further, CTX-induced increases in serum aspartate transanimase, alanine transaminase, and alkaline phosphatase were reversed by extract co-treatment, as were alterations in in situ formation/release of interferon (IFN)-, interleukin (IL)-2, granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-. Overall, this study indicated there were some protective effects from use of an extract of A.ferruginea against CTX-induced toxicities, in part through modulation of levels of anti-oxidants and pro-inflammatory cytokines.

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“…However, no mice receiving the treatment survived to the desired end point (Figure ). Although IFNγ is a potent activator of the Th1 system, it also induces Tregs and myeloid derived suppressor cells (MDSC) . These undesirable effects may be responsible for the limited success of the IFNγ therapy group.…”

Section: Discussionmentioning

confidence: 99%

Manipulation of the tumor microenvironment by cytokine gene transfection enhances dendritic cell‐based immunotherapy

et al. 2019

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The tumor microenvironment strongly influences clinical outcomes of immunotherapy.By transfecting genes of relevant cytokines into tumor cells, we sought to manipulate the microenvironment so as to elicit activation of T helper type 1 (Th1) responses and the maturation of dendritic cells (DCs). Using a synthetic vehicle, the efficiency of in vivo transfection of GFP-cDNA into tumor cells was about 7.5% by intratumoral injection and about 11.5% by intravenous injection. Survival was significantly improved by both intratumoral and intravenous injection of the plasmid containing cDNA of interferongamma, followed by intratumoral injection of DCs presenting the tumor antigens. Also, tumor growth was inhibited by these treatments. A more significant effect on survival and tumor growth inhibition was observed following injection of the plasmid containing cDNA of CD40 ligand, which is a potent inducer of DC-maturation. Furthermore, the co-injection of both IFNγ-and CD40 ligand-encoding cDNA-plasmids, followed by DC treatment, gave rise to further marked and enhancement, including 100% survival and more than 50% complete remission. This treatment regimen elicited significant increases in mature DCs and types of cells contributing to Th1 responses, and significant decreases in immune suppressor cells in the tumor. In the spleen, the treatment significantly increased activities of tumor-specific killer and natural killer cells, but no alteration was observed in mature DCs or suppressor cells. These results indicate that transfection of these cytokine genes into tumor cells significantly alter the tumor microenvironment and improve the therapeutic results of DC-based immunotherapy. K E Y W O R D Scancer immunotherapy, CD40 ligand, gene therapy, immunity, interferon-gamma, synthetic vehicle 6 |

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IFN-γ producing T cells contribute to the increase of myeloid derived suppressor cells in tumor-bearing mice after cyclophosphamide treatment

Cited by 16 publications

References 30 publications

Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response

Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response

Acacia ferrugineainhibits cyclophosphamide-induced immunosuppression and urotoxicity by modulating cytokines in mice

Manipulation of the tumor microenvironment by cytokine gene transfection enhances dendritic cell‐based immunotherapy

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